Management Of Gynecologic Cancers Research Articles

Use of a Flexible Inflatable Multi-Channel Applicator for Vaginal Brachytherapy in the Management of Gynecologic Cancer.

Evaluate use of novel multi-channel applicator (MC) Capri™ to improve vaginal disease coverage achievable by single-channel applicator (SC) and comparable to Syed plan simulation. Twenty-eight plans were evaluated from four patients with primary or recurrent gynecologic cancer in the vagina. Each received whole pelvis radiation, followed by three weekly treatments using HDR brachytherapy with a 13-channel MC. Upper vagina was treated to 5 mm depth to 1500 cGy/3 fractions with a simultaneous integrated boost totaling 2100 cGy/3 fractions to tumor. Modeling of SC and Syed plans was performed using MC scans for each patient. Dosimetry for MC and SC plans was evaluated for PTV700 cGy coverage, maximum dose to 2 cm(3) to bladder, rectum, as well as mucosal surface points. Dosimetry for Syed plans was calculated for PTV700 cGy coverage. Patients were followed for treatment response and toxicity. Dosimetric analysis between MC and SC plans demonstrated increased tumor coverage (PTV700 cGy), with decreased rectal, bladder, and contralateral vaginal mucosa dose in favor of MC. These differences were significant (p < 0.05). Comparison of MC and Syed plans demonstrated increased tumor coverage in favor of Syed plans which were not significant (p = 0.71). Patients treated with MC had no cancer recurrence or ≥grade 3 toxicity. Use of MC was efficacious and safe, providing superior coverage of tumor volumes ≤1 cm depth compared to SC and comparable to Syed implant. MC avoids excess dose to surrounding organs compared to SC, and potentially less morbidity than Syed implants. For tumors extending ≤1 cm depth, use of MC represents an alternative to an interstitial implant.

Mitochondrial dynamics regulating chemoresistance in gynecological cancers

Chemoresistance enables cancer cells to evade apoptotic stimuli and leads to poor clinical prognosis. It arises from dysregulation of signaling factors responsible for inducing cell proliferation and death and for modulating the microenvironment. In gynecologic cancers, p53 is a pivotal determinant of cisplatin sensitivity, while BCL-2 family members are associated with taxane sensitivity. Mitochondria fusion and fission dynamics are required for many mitochondrial functions and are also involved in mitochondria-mediated apoptosis, which is closely associated with chemosensitivity. Mitochondrial dynamics are controlled by a number of intracellular proteins, including fusion (Opa1 and mitofusion 1 and 2) and fission proteins (Drp1 and Fis1), which can be proapoptotic or antiapoptotic, depending on the cell types, status, and stimuli from the microenvironment. This paper describes the role of mitochondrial dynamics in the mechanism of chemoresistance and the evidence supporting a significant contribution of a hyperfusion state to chemoresistance in gynecological cancers. Moreover, we discuss our findings showing that enforced fission induces apoptosis of cancer cells and sensitizes them to chemotherapeutic agents. Understanding the regulation of mitochondrial dynamics in chemoresistance may provide insight into new biomarkers that better predict cancer chemosensitivity and may aid the development of effective therapeutic strategies for clinical management of gynecologic cancers.

Radiothérapie chez la personne âgée, recommandations pour la pratique clinique pour les principales localisations : cancers du sein, de la prostate et gynécologiques

Modifications of radiotherapy indications or schedules because of age could be discussed in view of a different evolution of the disease or because of specific toxicities. One important aim is to decrease the number of hospital transports. For breast cancer, the rate of local relapse after lumpectomy is lower in old patients; moreover, characteristics of the disease are often more favourable (hormonosensitivity, low grade). However, adjuvant irradiation decreases significantly the incidence of breast relapse and must be systematically proposed. Hypofractionnated schedules must be recommended; limited data are available for accelerated partial breast irradiation in old women and these techniques must not be used in routine. For low or intermediate risk prostate cancer, assessment of comorbidities is crucial before considering any invasive treatment. A life expectancy of at least 10 years is required if a curative approach, potentially toxic is proposed. In this case, radiotherapy is often the good choice, giving less sequelae than surgery. The indication of androgen deprivation must take into account cardiovascular and bone history. Management of gynaecological cancers must follow the same recommendations as in young women. Exclusive postoperative brachytherapy must be recommended in early stage endometrial carcinomas. Brachytherapy must be also systematically integrated in the radiotherapy program for cervix cancers, even in old women.

Extraperitoneal Lymphadenectomy in the Management of Gynecologic Cancer

The role of lymphadenectomy in the management of gynecologic malignancies has evolved as we have come to better understand the limitations of our current diagnostic tests and treatment paradigms for node-positive disease. The optimal surgical approach to lymphadenectomy is one that minimizes operative morbidity, permits rapid postoperative recovery, and leads to prompt initiation of adjuvant therapy without compromising oncologic outcomes. Initially, node status was assessed using a transperitoneal approach by laparotomy. However, the high complication rate associated with this procedure, particularly in combination with extended field radiation, led to the development of extraperitoneal approaches to lymphadenectomy. With the innovation and refinement of minimally invasive surgery, the effectiveness of laparoscopic and robotic extraperitoneal lymphadenectomy has now been established. This review describes the execution of the various extraperitoneal approaches to lymphadenectomy in gynecologic oncology surgical practice. The data comparing the adequacy and sensitivity of these and transperitoneal approaches for the assessment of nodal involvement are also presented. Further, the unique advantages of and complications associated with the extraperitoneal lymphadenectomy are discussed. Lastly, this review will highlight what we have learned about the diagnostic and therapeutic value of lymphadenectomy in the management of gynecologic malignancies as the extraperitoneal approach has been critically evaluated over time. Presently, the first phase III randomized controlled trials investigating these endpoints with consideration given to the various approaches to lymphadenectomy are ongoing.

Integrating Permanent Interstitial Brachytherapy Using Cesium-131 into the Primary Management of Gynecologic Malignancies: Bringing Back the Old School

Permanent interstitial brachytherapy (PIB) using free radiation seeds is an often forgotten modality that provides multiple distinct advantages. The relatively low initial dose rate and short half-life of Cesium-131 significantly reduces the exposure to the treating physician and involved medical staff compared to previously used permanent isotopes. Re-irradiation using Cesium-131 PIB has been described as a management option for recurrent disease. This report presents our experience incorporating its use in up-front management of Gyn malignancies. The records of 21 consecutive patients were retrospectively reviewed, all of whom were treated for a gynecologic malignancy using Cesium-131 PIB as a component of definitive therapy. Local failure was defined as a recurrence within the irradiated organ (vagina or vulva). Maximum doses to gross disease and normal tissues were calculated using equivalent dose at 2Gy per fraction (EQD2), outcomes were estimated from the time in months from the date of PIB, and toxicities were scored according to CTCAE v4.0. Reasons for performing PIB included a boost to gross disease for endometrioid adenocarcinoma (EAC) of the uterus (5), squamous cell carcinoma (SCC) of the cervix (1), vaginal SCC (3), vaginal melanoma (3), and vulvar SCC (2); and as a boost for close or positive margins in EAC (4), SCC of the cervix (1), and SCC of the vulva (2). Combined with a median dose of external beam RT of 45 Gy (range 30-64.8 Gy), the median dose delivered using PIB was 22 Gy (range 15-50 Gy) using a median 13 Cesium-131 sources (range 9-30), with median strength of 0.76 u/seed. The median area of PIB was 6 cm2 (range 2 - 19.25 cm2). All patients received their procedure as an outpatient. Sedation consisted of general anesthesia in 2 patients, and local anesthesia in 19. After a median follow-up period of 10.7 months (3-26.5 mos), there has been no local failures. All patients developed acute grade 1-2 mucosal reactions, and only 1 patient has demonstrated persistent grade 3 reactions beyond 6 months. Compared to equivalent plans using vaginal cylinders, equivalent tumoricidal doses of radiation could be delivered using Cs-131 PIB, while calculated maximum doses in EQD2 to normal tissues such as rectum and bladder could consistently be reduced by as much as 20% using PIB. PIB using Cs-131 is an effective treatment modality for incorporation into primary management of gynecologic cancers. The technique benefits from a low rate of morbidity and a very high local control.

Emotional and sexual concerns in women undergoing pelvic surgery and associated treatment for gynecologic cancer.

The surgical management of gynecologic cancer can cause short- and long-term effects on sexuality, emotional well being, reproductive function, and overall quality of life (QoL). Fortunately, innovative approaches developed over the past several decades have improved oncologic outcomes and reduced treatment sequelae; however, these side effects of treatment are still prevalent. In this article, we provide an overview of the various standard-of-care pelvic surgeries and multimodality cancer treatments (chemotherapy and radiation therapy) by anatomic site and highlight the potential emotional and sexual consequences that can influence cancer survivorship and QoL. Potential screening tools that can be used in clinical practice to identify some of these concerns and treatment side effects and possible solutions are also provided. These screening tools include brief assessments that can be used in the clinical care setting to assist in the identification of problematic issues throughout the continuum of care. This optimizes quality of care, and ultimately, QoL in these women. Prospective clinical trials with gynecologic oncology populations should include patient-reported outcomes to identify subgroups at risk for difficulties during and following treatment for early intervention.

Paradigm Shift in the Management of Gynaecological Cancers

In this review we highlight novel aspects of diagnostic imaging in gynaecological cancers, the paradigm shift in the surgical management of certain female pelvic cancers, as well as potential new molecular targeted therapies. In the last decade, ultra-radical surgery has been shown to increase survival in advanced ovarian cancer (OVC) when extended surgical procedures are included during primary cytoreductive surgery or at interval debulking procedures after neoadjuvant chemotherapy. In cervical cancer (CVC) and endometrial cancer (EMC) endoscopic (laparoscopic or robotic) operations have been shown to significantly reduce the morbidity without altering the cancer-related survival. Although the sentinel lymph node concept is already established in early-stage vulvar cancer, its diagnostic accuracy in EMC and CVC is still under debate. Novel molecular targeted therapies including blocking agents against new blood vessel formation (anti-angiogenesis) and polyadenosine diphosphate ribose polymerase inhibitors have been shown to prolong the progression-free survival in advanced OVC. Other molecular therapies, single or combined, are under investigation in OVC and EMC.

Neoadjuvant chemotherapy in gynaecological cancers – Implications for staging

The management of advanced gynaecological cancers remains a therapeutic challenge. Neoadjuvant chemotherapy has been used to reduce tumour size, thus facilitating subsequent local treatment in the form of surgery or radiation. For advanced epithelial ovarian cancer, data from several non-randomized and one randomized studies indicate that neoadjuvant chemotherapy followed by interval debulking surgery is a reasonable approach in patients deemed inoperable. Such an approach results in optimum debulking (no visible tumour) in approximately 40% of the patients with reduced operative morbidity. Overall and progression free-survival is comparable to the group treated with primary debulking surgery followed by chemotherapy. Neoadjuvant chemotherapy followed by surgery is associated with improved survival for women with stage IB2-IIA cervix cancer. There is a resurgence of interest for using short-course neoadjuvant chemotherapy prior to concurrent chemo-radiation. Currently, this is being tested in randomized trials.

Sentinel lymph node biopsy in the management of gynecologic cancer.

To summarize current knowledge and recent advances in sentinel lymph node (SLN) concept in the three most frequent gynecological cancers. In cervical cancer, SLN biopsy and ultrastaging has high sensitivity in lymph node staging in patients with bilaterally detected SLN. The presence of micrometastasis is associated with shortened survival. In endometrial cancer, SLN biopsy incorporating an institutional mapping algorithm and ultrastaging has been shown to significantly reduce false-negative rates and increase sensitivity and negative predictive value. SLN biopsy and ultrastaging is useful in current management of patients with early-stage cervical cancer for multiple reasons, such as the reliable detection of key lymph nodes, identification of micrometastasis and intraoperative triage of patients. Although a complete or selective pelvic and paraaortic lymphadenectomy for adequate staging remains the standard treatment approach in patients with early-stage endometrial cancer, SLN biopsy has been shown to be safe and effective in detecting lymph node metastases. The application of the SLN procedure is safe in patients with early-stage unifocal squamous cell cancer of the vulva (<4 cm) and no suspicious enlarged lymph nodes at imaging.

Asian Society of Gynecologic Oncology International Workshop 2014.

The Asian Society of Gynecologic Oncology International Workshop 2014 on gynecologic oncology was held in Asan Medical Center, Seoul, Korea on the 23rd to 24th August 2014. A total of 179 participants from 17 countries participated in the workshop, and the up-to-date findings on the management of gynecologic cancers were presented and discussed. This meeting focused on the new trends in the management of cervical cancer, fertility-sparing management of gynecologic cancers, surgical management of gynecologic cancers, and recent advances in translational research on gynecologic cancers.

Delayed Presentation of Patients with Gynaecological Malignancies in Kano, North-Western Nigeria

The diagnosis and management of gynaecological cancers are still challenging in low- and middle-income countries. In patients with gynaecological malignancies delay at any point increases morbidity and mortality. This study evaluated the factors that may delay presentation, diagnosis and treatment of patients with malignant gynaecological cancers, and described the duration of each delay. It was a prospective cross-sectional study. A total number of 96 patients diagnosed to have gynaecological malignancy were enrolled in the study between the April 2014 and April 2015. The median age was 47.5 years (range of 18 - 84 years). The diagnoses on admission were cervical malignancy 34 (35.42%), ovarian malignancy 32 (33.33%), chorio carcinoma 15 (15.63%), cancers of uterine body (endometrial and leiomyosarcoma) 10 (10.42%) and vulval malignancies 5 (5.2%). Majority of the patients 65 (67.7%) presented late at either stage III or IV. At presentation, 36 patients (37.5%) had severe anaemia; 10 patients (10.41%) had obstructive uropathy; 3 (3.13%) developed fistula; 19 (19.79%) died on admission from complication of their disease. Most patients 61 (63.54%) had delayed presentation of more than 90 days (“patients delay”). Time in decision ranged between 3 days to maximum of 2920 days and median of 150 days. 58 (60.42%) gave a reason for such delay as lack of knowledge of their presenting symptoms, as a warning sign of possible malignancy; 80 (83.33%) had delay in diagnosis (“doctor delay”); 40 (41.67%) reported that the medical practitioner did not make referral to the center with available gynaecological services; “hospital delay” was observed in 66 (68.75%) of patients. The reason for delayed treatment in 35 (36.46%) of patients was severe patients condition that warrant stabilization (blood transfusion and dialysis) and 29 (30.21%) could not afford the treatment. Late presentation is a great problem in the management of oncological patients in this environment. High cost of care is the major challenge for the patients and gynaecologist in north-western part of Nigeria.

Adherence to Guidelines in Gynecologic Cancer Surgery

The purpose of this study is to review the available evidence documenting the prognostic role of adherence to guidelines in gynecologic cancers. A systematic review of the PubMed database using "guideline," "adherence," and "cancer" was carried out on February 25, 2014. Two thousand one hundred twenty-three publications were identified. Only publications addressing the question of adherence to recommendations regarding surgical care and multidisciplinary management of gynecologic cancers were selected. Six studies were identified in endometrial cancer, 4 in ovarian cancer, and none in cervical cancer. Adoption of guidelines is an effective tool for disease control and must consequently be considered as a process measure of quality cancer care. It is urgent to develop reliable and reproducible tools to assess adherence to guidelines based on level 1 evidence in gynecologic cancer then to carry out investigations to document the prognostic impact of compliance with guidelines. The time has come to include adherence to guidelines in quality assurance programs.

Management of gynecological cancers during pregnancy.

The diagnosis of a gynecological malignancy during pregnancy is rare but not uncommon. Cancer treatment during pregnancy is possible, but both maternal and fetal interests need to be respected. Different treatment plans may be justifiable and multidisciplinary treatment is advised. Clinical trials are virtually impossible, and current evidence is mainly based on small case series and expert opinion. Individualization of treatment is necessary and based on tumor type, stage, and gestational age at time of diagnosis. Termination of pregnancy is not necessary in most cases. Surgery and chemotherapy (second trimester and onwards) are possible types of treatment during pregnancy. Radiotherapy of the pelvic area is not compatible with an ongoing pregnancy. This article discusses the current recommendations for the management of gynecological malignancies (cervical, ovarian, and vulvar cancers) during pregnancy.

Abstract 3758: Inhibition of ATR, but not ATM, sensitizes gynecologic cancer cells to cisplatin

Abstract Resistance to platinum-based therapies remains a major hurdle in the management of gynecologic (GYN) cancer especially in ovarian cancer. Platinum such as cisplatin damages DNA by inducing DNA crosslinks that stalls DNA replication forks where significant accumulation of single-stranded DNA from persistently stalled replication forks could ultimately lead to double strand breaks and activation of apoptosis. Ataxia telangiectasia mutated (ATM) and ATM and Rad-3-related (ATR) are two main DNA damage response (DDR) protein kinases that recognize genotoxic stress and function to initiate cell cycle arrest and DNA repair mechanisms. We hypothesized by combining genotoxic stress with inhibition of DDR kinases ATR and/or ATM, therapeutic response of GYN cancer cells to platinum-based chemotherapy could be improved. To test our hypothesis, we assessed cell survival of multiple GYN cell lines including ovarian (A2780, A2780-CP20, OVCAR3), endometrial (KLE, HEC1B), and cervical (HELA, SIHA) carcinoma cells exposed to cisplatin along with ATR inhibitor (ETP-46464) and/or ATM inhibitor (KU55933). We observed inhibition of ATR significantly enhanced cisplatin induced cell death in all seven cell lines tested, resulting in 65 - 96% increased sensitivity to cisplatin. Inhibition of ATM did not sensitize GYN cancer cells to cisplatin and cells were not further sensitized by co-inhibition of ATM and ATR beyond that observed by inhibition of ATR alone. DDR signaling was assessed by immunoblotting in cells exposed to cisplatin with or without the presence of ETP-46464 and/or KU55933 where elevated levels of phospho-ATM (Ser1981), phospho-Chk2 (Thr68) and phospho-Chk1 (Ser345) observed in cisplatin treated cells were attenuated in cells that were co-treated with cisplatin and ETP-46464. In addition, increased levels of cleaved PARP1 and caspase 3 were observed in cisplatin-treated, ATR-inhibited cells, suggesting the enhancement of cisplatin induced cell death with ATR inhibition occurs through elevated apoptosis. Further, no differential effect was observed in GYN cancer cells harboring wild type (A2780, OVCAR3, HELA, SIHA) or mutant (CP20, KLE, HEC1B) TP53. These data support further investigation of pharmacologic inhibitors of ATR in combination with existing platinum based therapeutics for treating GYN cancer. Citation Format: Pang-Ning Teng, Nicholas W. Bateman, Chad A. Hamilton, G. Larry Maxwell, Christopher J. Bakkenist, Thomas P. Conrads. Inhibition of ATR, but not ATM, sensitizes gynecologic cancer cells to cisplatin. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3758. doi:10.1158/1538-7445.AM2014-3758

Use of Simultaneous Integrated Boost Regimen With Flexible Inflatable Multi-Channel Versus Single Channel and Syed Applicator in the Management of Gynecologic Cancer

Use of Simultaneous Integrated Boost Regimen With Flexible Inflatable Multi-Channel Versus Single Channel and Syed Applicator in the Management of Gynecologic Cancer

Single-port access laparoscopic re-staging with bilateral salpingo-oophorectomy and bilateral pelvic lymph node dissection for endometrial cancer

Abstract Laparo-endoscopic single site surgery (LESS) is a relatively new technique that has been described in recent medical literature to be feasible in the management of benign gynaecological conditions. However, the use of this technique in the management of gynaecological cancers is still controversial. In this case report, we describe the first single port laparoscopic pelvic lymphadenectomy performed in Singapore. This involved a patient who was diagnosed with endometrial cancer after a vaginal hysterectomy for uterovaginal prolapse.

Gynecology and Obstetrics has Entered Modern Times: Perspectives and Challenges.

Gynecology and Obstetrics has Entered Modern Times: Perspectives and Challenges.

Dosimetric Comparison of Simultaneous Integrated Boost Regimen Using Flexible Inflatable Multi-Channel Versus Single Channel Vaginal Applicator in the Management of Gynecologic Cancer

overall survival (2-yr overall survival 94% vs 63%, p50.002) following definitive salvage therapy. Conclusions: Salvage image-based HDRB shows excellent tumor control and acceptable morbidity for vaginal recurrences of endometrial cancer. Anticipated salvage rates must be taken in the context of primary risk factors including the widely quoted salvage rates from PORTEC 1 which included primarily intermediate risk stage I patients.

Editorial introductions

Editorial introductions

Challenges associated with the management of gynecological cancers in a tertiary hospital in South East Nigeria.

BackgroundThere are reports of increasing incidence of gynecological cancers in developing countries and this trend increases the need for more attention to gynecological cancer care in these countries.ObjectiveThe purpose of this study was to describe the presentation and treatment of gynecological cancers and identify barriers to successful gynecological cancer treatment in a tertiary hospital in South East Nigeria.MethodsThis study was a retrospective longitudinal analysis of the presentation and treatment of histologically diagnosed primary gynecological cancers from 2000 to 2010. Analysis was by descriptive and inferential statistics at the 95% level of confidence using Statistical Package for the Social Sciences version 17 software.ResultsRecords of 200 gynecological cancers managed during the study period were analyzed. Over 94% of cervical cancers presented in advanced stages of the disease and received palliative/symptomatic treatment. Only 1.9% of cervical cancer patients had radical surgical intervention, and postoperative mortality from these radical surgeries was 100%. Approximately 76% of patients with ovarian cancer had debulking surgery as the mainstay of treatment followed by adjuvant chemotherapy. Postoperative mortality from ovarian cancer surgery was 63%. Cutting edge cytotoxic drugs were not used as chemotherapy for ovarian and chorionic cancers. Compliance with chemotherapy was poor, with over 70% of ovarian cancer patients failing to complete the prescribed courses of chemotherapy. Most patients with endometrial and vulval cancers had only surgical treatment, as compliance with follow-up for adjuvant chemotherapy or radiotherapy was poor. Functional radiotherapy facilities were not available at the center during the study period, thereby necessitating external referrals to centers hundreds of kilometers away.ConclusionLate presentation of cases, noncompliance with treatment regimens, lack of use of cutting edge cytotoxic drugs, the poor outcome of radical surgeries, and lack of a functional radiotherapy facility combined to create a very difficult gynecological cancer care environment at the study center.